7-101237434-A-C

Variant names:

• chr7-101237434-A-C
• rs1562905689
• NM_014343.3:c.148T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014343.3(CLDN15):​c.148T>G​(p.Phe50Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLDN15 NM_014343.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.310

Genes affected

CLDN15 (HGNC:2036): (claudin 15) This gene encodes a member of the claudin family. Claudins are integral membrane proteins and components of tight junction strands. Tight junction strands serve as a physical barrier to prevent solutes and water from passing freely through the paracellular space between epithelial or endothelial cell sheets, and also play critical roles in maintaining cell polarity and signal transductions. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22235167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLDN15	NM_014343.3	c.148T>G	p.Phe50Val	missense_variant	Exon 1 of 5	ENST00000308344.10	NP_055158.1
CLDN15	NM_001185080.2	c.148T>G	p.Phe50Val	missense_variant	Exon 2 of 6		NP_001172009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLDN15	ENST00000308344.10	c.148T>G	p.Phe50Val	missense_variant	Exon 1 of 5	1	NM_014343.3	ENSP00000308870.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.148T>G (p.F50V) alteration is located in exon 2 (coding exon 1) of the CLDN15 gene. This alteration results from a T to G substitution at nucleotide position 148, causing the phenylalanine (F) at amino acid position 50 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Uncertain	0.50	D;D;T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.55	N;N;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.73	N;N;.;N;N
REVEL	Benign	0.24
Sift	Benign	0.45	T;T;.;T;T
Sift4G	Benign	0.51	T;T;T;T;.
Polyphen		0.024	B;B;B;.;.
Vest4		0.18
MutPred		0.58		Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);Loss of loop (P = 0.2237);
MVP		0.67
MPC		0.46
ClinPred		0.23	T
GERP RS		2.4
Varity_R		0.075
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1562905689; hg19: chr7-100880715;